Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer

Akter, Hafeza; Park, Min; Kwon, Oh‐Seung; Song, Eun Joo; Park, Won-Sang; Kang, Min‐Jung

doi:10.1007/s13277-015-3282-9

Cited by 57 publications

(55 citation statements)

References 35 publications

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“…NTS also participates in tumor migration and invasion. In prostate cancer, NTS stimulates tumor invasion rather than growth [20, 21]. However, the expression of NTS in HCC has been rarely explored because NTS is absent in healthy adult liver.…”

Section: Introductionmentioning

confidence: 99%

NTS/NTR1 co-expression enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma

Long

Zhang

et al. 2016

Oncotarget

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Neurotensin (NTS) is a neuropeptide distributed in central nervous and digestive systems. In this study, the significant association between ectopic NTS expression and tumor invasion was confirmed in hepatocellular carcinoma (HCC). In primary HCC tissues, the NTS and neurotensin receptor 1 (NTR1) co-expression (NTS+NTR1+) is a poor prognostic factor correlated with aggressive biological behaviors and poor clinical prognosis. Enhanced epithelial-to-mesenchymal transition (EMT) features, including decreased E-cadherin, increased β-catenin translocation and N-cadherin expression, were identified in NTS+NTR1+ HCC tissues. Varied NTS-responsible HCC cell lines were established using NTR1 genetically modified Hep3B and HepG2 cells which were used to elucidate the molecular mechanisms regulating NTS-induced EMT and tumor invasion in vitro. Results revealed that inducing exogenous NTS stimulation and enhancing NTR1 expression promoted tumor invasion rather than proliferation by accelerating EMT in HCC cells. The NTS-induced EMT was correlated with the remarkable increase in Wnt1, Wnt3, Wnt5, Axin, and p-GSK3β expression and was significantly reversed by blocking the NTS signaling via the NTR1 antagonist SR48692 or by inhibiting the activation of the Wnt/β-catenin pathway via specific inhibitors, such as TSW119 and DKK-1. SR48692 also inhibited the metastases of NTR1-overexpressing HCC xenografts in the lungs in vivo. This finding implied that NTS may be an important stimulus to promote HCC invasion and metastasis both in vitro and in vivo, and NTS signaling enhanced the tumor EMT and invasion potentials by activating the canonical Wnt/β-catenin signaling pathway. Therefore, NTS may be a valuable therapeutic target to prevent tumor progression in HCC.

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Section: Introductionmentioning

confidence: 99%

NTS/NTR1 co-expression enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma

Long

Zhang

et al. 2016

Oncotarget

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“…5A and B, OZ treatment significantly reduced the invasive ability of MGC803 cells compared with the vehicle-treated group (P<0.05). As MMP9 has been previously reported to have an important role in gastric cancer invasion (17), the present study also investigated the expression level of MMP9 protein by western blot analysis and demonstrated that MMP9 expression was significantly downregulated in the OZ treatment group compared with the vehicle treatment group (P<0.05; Fig. 5C).…”

Section: Resultsmentioning

confidence: 69%

“…These findings may elucidated the underlying mechanism whereby OZ functions as a tumor suppressor by inducing apoptosis. In addition, previous reports indicated that MMP9, which is regulated by NF-κB (40), had an important role in the invasion of gastric cancer cells (17,41). The current study demonstrated that OZ significantly inhibited the expression of MMP9, which may be one of the molecular mechanisms by which OZ inhibited the invasion of gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Expression and function of transforming growth factor-β-activated protein kinase 1 in gastric cancer

Yang

Qiu

Tang

et al. 2017

Molecular Medicine Reports

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The present study aimed to investigate the expression and role of transforming growth factor (TGF) -β-activated protein kinase 1 (TAK1) in human gastric cancer. Immunohistochemistry was performed to investigate the expression of TAK1 in surgical specimens of human gastric cancer tissue and adjacent normal tissue. The association between TAK1 and clinicopathologic factors was analyzed and the association between TAK1 expression and the overall survival rates was evaluated using Kaplan-Meier curves. In addition, the effect of the TAK1 selective inhibitor 5Z-7-oxozeaenol (OZ) on the biological characteristics of MGC803 human gastric cancer cells in vitro were investigated. The role of TAK1 in gastric cancer cell proliferation, apoptosis and invasion were determined by cell proliferation assays, flow cytometry analysis and transwell invasion assays, respectively. The findings of the present study demonstrated that the positive expression rate of TAK1 in gastric cancer and adjacent normal tissues was 70.5 and 25.9%, respectively. Furthermore, TAK1 expression was significantly associated with advanced N stage and pathological stage (P<0.05). Survival analysis of 139 patients with gastric cancer indicated a lower overall survival rate of patients in the TAK1-positive group compared with the TAK1-negative group (P<0.05). In addition, treatment with the TAK1 selective inhibitor OZ reduced the proliferation and invasion abilities of MGC803 cells and significantly reduced the expression levels of phosphorylated-TAK1 (Thr187), nuclear p65, cyclin D1, Bcl-2 apoptosis regulator and matrix metallopeptidase (MMP)9 (P<0.05). OZ treatment significantly increased the expression levels of cytosolic cytochrome c and cleaved caspase 3 and the apoptosis rate in MGC803 cells (P<0.05). In conclusion, these findings suggest that increased TAK1 expression may be involved in the progression of gastric cancer; therefore, TAK1 may be used as a future therapeutic target for gastric cancer treatment.

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“…It was used in scientific research to explore the physical or pathological functions, especially antitumour activities of NTS/NTSR1 signaling. In addition, SR48692 showed antitumour activities in multiple tumours, including melanoma (Zhang et al , 2014), prostate cancer (Baxendale et al , 2013), gastric cancer (Akter et al , 2015), pancreatic carcinoma (Iwase et al , 1997) and so on. These evidences indicated that SR48692 might be a potent drug for cancer treatments.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma

et al. 2017

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Backgroud:Glioblastoma is a kind of highly malignant and aggressive tumours in the central nervous system. Previously, we found that neurotensin (NTS) and its high-affinity receptor 1 (NTSR1) had essential roles in cell proliferation and invasiveness of glioblastoma. Unexpectedly, cell death also appeared by inhibition of NTSR1 except for cell cycle arrest. However, the mechanisms were remained to be further explored.Methods:Cells treated with SR48692, a selective antagonist of NTSR1, or NTSR1 shRNA were stained with Annexin V-FITC/PI and the apoptosis was assessed by flow cytometry. Cytochrome c release was detected by using immunofluorescence. Mitochondrial membrane potential (MMP, ΔΨm) loss was stained by JC-1 and detected by immunofluorescence or flow cytometry. Apoptosis antibody array and microRNA microarray were performed to seek the potential regulators of NTSR1 inhibition-induced apoptosis. Interaction between let-7a-3p and Bcl-w 3′UTR was evaluated by using luciferase assay.Results:SR48692 induced massive apoptosis, which was related to mitochondrial cytochrome c release and MMP loss. Knockdown of NTSR1 induced slight apoptosis and significant MMP loss. In addition, NTSR1 inhibition sensitised glioblastoma cells to actinomycin D or doxorubicin-induced apoptosis. Consistently, NTSR1 inhibition-induced mitochondrial apoptosis was accompanied by downregulation of Bcl-w and Bcl-2. Restoration of Bcl-w partly rescued NTSR1 deficiency-induced apoptosis. In addition, NTSR1 deficiency promoted higher let-7a-3p expression and inhibition let-7a-3p partly rescued NTSR1 inhibition-induced apoptosis. In addition, let-7a-3p inhibition promoted 3′UTR activities of Bcl-w and the expression of c-Myc and LIN28, which were the upstream of let-7a-3p, decreased after NTSR1 inhibition.Conclusions:NTSR1 had an important role in protecting glioblastoma from intrinsic apoptosis via c-Myc/LIN28/let-7a-3p/Bcl-w axis.

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Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer

Cited by 57 publications

References 35 publications

NTS/NTR1 co-expression enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma

NTS/NTR1 co-expression enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma

Expression and function of transforming growth factor-β-activated protein kinase 1 in gastric cancer

Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma

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